Project Summary Acute leukemias are identified according to their lineage of origin. Clinical diagnosis involves close evaluation of cell morphology and characteristic patterns of cell markers. With technical advances allowing for simultaneous evaluation of more and more markers, increasing numbers of leukemias show either mixed or ambiguous lineage characteristics. Biphenotypic Acute Leukemia (BAL) in particular highlights the limitations of current methodologies, displaying markers characteristic of both myeloid and lymphoid lineages. Analysis of the initial 5 BALs using DNA methylation profiling shows a range of lineage characteristics, with some more similar to acute myeloid leukemia (AML) specimens, and some more similar to acute lymphoblastic leukemia (ALL) specimens. We seek to characterize the lineage of BAL more precisely by developing a method to `deconvolve' lineage characteristics of an individual specimen. Preliminarily, it has correctly described in vitro cell mixtures as well as lineage features of known acute leukemia samples. Our goal is to translate a more precise understanding of BAL into novel therapeutic approaches for this devastating disease. Epigenetic regulators including DNMT3A and IDH1/2 are among the most commonly mutated genes in BAL. Recently, the FDA has approved the use of an IDH2 inhibitor in relapsed AML. Interestingly, our preliminary results indicate that IDH mutated AML displays epigenetically mixed lineage characteristics similar to BALs. In addition, patient samples with co-occurring IDH / DNMT3A mutations exhibit increased sensitivity to MEK inhibition in vitro. We seek to expand this study to evaluate the efficacy of dual IDH / MEK pathway inhibition both in vitro and in vivo using patient derived xenograft models of BAL. These studies will be led by Dr. Jacob Glass, a junior faculty member at Memorial Sloan Kettering Cancer Center under the dual mentorship of Dr. Ross Levine at Memorial Sloan Kettering and Olivier Elemento at Weill Cornell Medical Center. Dr. Levine is a leader in leukemia research with an established track record of effectively, rapidly mentoring former trainees into independence. Dr. Elemento is a leader in precision oncology with a track record of developing novel bioinformatic methods and technologies to assist therapeutic discovery. The Memorial Sloan Kettering Cancer Center and Human Oncology and Pathogenesis program offers an exceptional environment for cultivating a developing career in translational cancer research. To achieve the long-term goal of becoming an independent investigator, Dr. Glass has developed a structured curriculum of activities aimed at broadening his knowledge base, expanding his technical repertoire, and developing leadership skills and has assembled an advisory committee of leading scientists.